Estrogen receptor a (ERa) masculinizes male behavior, which is typically associated with low levels of prosocial (positive) behavior, such as formation of long-term pair bonds and parental care. Based upon this I completed a series of experiments to test the hypothesis that the low level of ERa observed in specific regions of the CNS of highly social males is necessary for/permits the expression of high levels of positive social (prosocial) behavior. An adeno-associated viral vector (AAV) containing ERa cDNA was used to increase the expression of ERa in the medial amygdala (MeA) of the socially monogamous male prairie vole (Microtus ochrogaster) (supported by R21-MH068278). The MeA is part of the "social neural circuit" and also influences the "reward system." Therefore, a change in the MeA could have a major impact on the expression of social behavior. The results supported the hypothesis, as increasing ERa decreased spontaneous alloparental care and disrupted the formation of a heterosexual partner preference. While these results indicate that low levels of ERa are necessary for males to express high levels of prosocial behavior the next critical piece is to demonstrate that decreasing ERa in a male that typically does not display high levels of prosocial behavior will increase the expression of prosocial behavior. The first goal of this study is to use AAV containing ERa RNAi (which inhibits the expression of ERa) to reduce/inhibit the expression of ERa in the MeA of male meadow voles (Microtus pennsylvanicus). Following the reduction of ERa, males will be tested for the expression of prosocial behavior, alloparental and heterosexual social preference, and male/male aggression with the prediction being that ERa minus males will display increased social behavior and decreased aggression. The second goal of this study is to determine if a reduction in ERa increases the ability of arginine vasopressin (AVP) to stimulate the expression of male prosocial behavior. Changes in ERa may directly regulate the expression of male prosocial behavior, but it may also influence the expression of social behavior by regulating the response to AVP. AVP has been shown to regulate a number of male social behaviors and many of the effects of AVP are steroid dependent. Therefore, a reduction in ERa may increase male prosocial behavior by "permitting" the social effects of AVP. The results from these studies will provide significant insight into the regulation of male social behavior. This information is vital as many social pathologies and mental health conditions are associated with either a lack of social or atypical social behavior, and understanding the mechanisms regulating social behavior will aid in developing potential treatments. PUBLIC HEALTH RELEVANCE: Estrogen receptor alpha (ERa) is involved in the masculinization of male behavior. The goal of this study is to test the hypothesis that a reduction of ERa in areas of the brain that regulate the expression of social behavior is necessary for males to express high levels of positive/affliative behavior, such as pair bond formation and parental care. This will be accomplished by inhibiting the expression of ERa in male rodents (meadow voles) that do not typically display high levels of social behavior. Understanding the regulation of social behavior is important as many mental health pathologies are associated with deficits or inappropriate expression of social behavior. [unreadable] [unreadable] [unreadable]